WO 95/10516, published Apr. 20, 1995 discloses tricyclic compounds useful for inhibiting farnesyl protein transferase.
In view of the current interest in inhibitors of farnesyl protein transferase, a welcome contribution to the art would be compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention.
This invention provides compounds useful for the inhibition of farnesyl protein transferase (FPD. The compounds of this invention are represented by the formula: 
or a pharmaceutically acceptable salt or solvate thereof, wherein:
a represents N or NOxe2x80x94;
R1 and R3 are the same or different halo atom;
R2 and R4 are selected from H and halo, provided that at least one of R2 and R4 is H;
the dotted line (---) represents an optional bond;
X is N, C when the optional bond is present, or CH when the optional bond is absent;
T is a substituent selected from: 
wherein:
A represents xe2x80x94(CH2)bxe2x80x94;
B represents xe2x80x94(CH2)dxe2x80x94;
b and d are independently selected from: 0, 1, 2, 3, or 4 such that the sum of b and d is 3 or 4; and
Y is selected from: O, S, SO, or SO2; 
wherein:
D represents xe2x80x94(CH2)exe2x80x94;
E represents xe2x80x94(CH2)fxe2x80x94;
e and f are independently selected from: 0, 1, 2, or 3 such that the sum of e and f is 2 or 3; and
Z is O; 
wherein:
F represents xe2x80x94(CH2)gxe2x80x94;
G represents xe2x80x94(CH2)hxe2x80x94;
U represents xe2x80x94(CH2)ixe2x80x94;
h represents 1, 2, or 3
g and i are independently selected from: 0, 1 or 2 such that the sum of h, g and i is 2 or 3; and
V and W are independently selected from O, S, SO, or SO2; 
wherein:
the dotted line (---) represents an optional bound:
k is 1 or 2 such that when the optional bond is present k represents 1, and when the optional double bond is absent then k represents 2;
R5, R6, R7 and R8 are the same alkyl (preferably methyl); or
R5 and R7 are the same alkyl (preferably methyl), and R6 and R8 are H; 
wherein:
the dotted lines (---) represent optional bonds 1 and 2 such that optional bonds 1 and 2 are both present, or optional bonds 1 and 2 are both absent;
Y represents O, S, SO, or SO2; 
wherein:
Y represents O, S, SO, or SO2; 
wherein:
R9 is selected from: xe2x80x94CN, xe2x80x94CO2H, or xe2x80x94C(O)N(R10)2;
each R10 is the same or diferent alkyl group (preferably, methyl); 
wherein:
I represents xe2x80x94(CH2)mxe2x80x94;
m represents 2 or 3;
Y represents O, S, SO, or SO2; and
R11 represents alkyl (preferably ethyl); 
The compounds of this invention: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro; (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.
The compounds of this invention inhibit farnesyl protein transferase and the farnesylation of the oncogene protein Ras. Thus, this invention further provides a method of inhibiting farnesyl protein transferase, (e.g., ras farnesyl protein transferase) in mammals, especially humans, by the administration of an effective amount of the tricyclic compounds described above. The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers described below.
This invention provides a method for inhibiting or treating the abnormal growth of cells. including transformed cells, by administering an effective amount of a compound of this invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.
This invention also provides a method for inhibiting or treating tumor growth by administering an effective amount of the tricyclic compounds, described herein, to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting or treating the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds. Examples of tumors which may be inhibited or treated include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, breast cancer and prostate cancer.
It is believed that this invention also provides a method for inhibiting or treating proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genesxe2x80x94i.e., the Ras gene itself is not activated by mutation to an oncogenic formxe2x80x94with said inhibition or treatment being accomplished by the administration of an effective amount of the tricyclic compounds described herein, to a mammal (e.g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, lck, and fyn), may be inhibited or treated by the tricyclic compounds described herein.
The tricyclic compounds useful in the methods of this invention inhibit or treat the abnormal growth of cells. Without wishing to be bound by theory, it is believed that these compounds may function through the inhibition of G-protein function, such as ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer. Without wishing to be bound by theory, it is believed that these compounds inhibit ras farnesyl protein transferase, and thus show antiproliferative activity against ras transformed cells.
As used herein, the following terms are used as defined below unless otherwise indicated:
MH+xe2x80x94represents the molecular ion plus hydrogen of the molecule in the mass spectrum:
Et (or ET)xe2x80x94represents ethyl (C2H5);
alkylxe2x80x94represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms;
halo-represents fluoro, chloro, bromo and iodo;
The following solvents and reagents are referred to herein by the abbreviations indicated: ethanol (EtOH); methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoroacetic anhydride (TFAA); 1-hydroxybenzotriazole (HOBT); 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (DEC); diisobutylaluminum hydride(DIBAL); and 4-methylmorpholine (NMM).
The positions in the tricyclic ring system are: 
Preferred halo atoms for R1, R2, R3, and R4 in Formula 1.0 are selected from: Br, Cl or I, with Br and Cl being preferred.
Compounds of Formula 1.0 include compounds of the formula: 
wherein R1 and R3 are the same or different halo. Preferably, for these dihalo compounds, R1 and R3 are independently selected from Br or Cl, and more preferably R1 is Br and R3 is Cl. Preferably, X is CH or N, with CH being more preferred.
Compounds of Formula 1.0 include compounds of Formulas 1.1 and 1.2: 
wherein R1, R3 and R4 in Formula 1.1 are halo, and R1, R2 and R3 in Formula 1.2 are halo. Compounds of Formula 1.1 are preferred.
Preferably, in Formula 1.1, R1 is Br, R3 is Cl, and R4 is halo. More preferably, in Formula 1.1, R1 is Br, R3 is Cl, and R4 is Br.
Preferably, in Formula 1.2, R1 is Br, R2 is halo, and R3 is Cl. More preferably, in Formula 1.1, R1 is Br, R2 is Br, and R3 is Cl.
Preferably, for compounds of Formulas 1.1 and 1.2, X is CH or N. For compounds of Formula 1.1, X is preferably CH.
Preferably, for the compounds of this invention, the optional bond between positions 5 and 6 (i.e., C5-C6) in the tricyclic system is absent.
Also, preferably, for the compounds of this invention, substituent a in Ring I represents N.
Those skilled in the art will appreciate that compounds of Formula 1.0 include compounds of Formulas 1.3 and 1.4: 
wherein X is CH or N, with compounds of 1.3 being preferred for compounds of Formula 1.1, and with compounds of Formula 1.4 being preferred for componds of Formula 1.2.
Thus, compounds of the invention include compounds of the formulas: 
Compounds of Formula 1.9 are preferred.
Preferably substituent T is 
More preferably, substituent T is the substituent of Formula 2.0 wherein the sum of b and d is 4. Most preferably b is 2 and d is 2 forming the group: 
Preferably, Y is O.
Examples of Formula 2.0 also include substituents wherein: (a) the sum of b and d is 3, wherein b is 3 and d is 0; (b) the sum of b and d is 4, wherein b is 4 and d is 0; (c) the sum of b and d is 4, wherein b is 3 and d is 1; and (d) the sum of b and d is 3, wherein b is 2 and d is 1. For these examples Y is preferably O.
Examples of Formula 2.0 include: 
includes substituents wherein: (a) the sum of e and f is 3, wherein e is 3 and f is 0; (b) the sum of e and f is 2, wherein e is 1 and d is 1; and (c) the sum of e and f is 2, wherein e is 2 and f is 0.
Examples of Formula 3.0 include: 
includes substituents wherein: g is 0, h is 2, and i is 1. Preferably, V and W are O. For example, Formula 4.0 includes the substituent 
includes the substituents: 
includes the substituents: 
Representative compounds of the invention include compounds of the formula: 
wherein R12 is selected from: 
Those skilled in the art will appreciate that substituent R12 is the same as substituent 
Representative compounds of this invention also include: 
Representative compounds of the invention also include: 
Lines drawn into the ring systems indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.
Certain compounds of the invention may exist in different isomeric (e.g., enantiomers and diastereoisomers) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.
Certain tricyclic compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines. hydroxyalkylamines, N-methylglucamine and the like.
Certain basic tricyclic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Compounds of the invention may be prepared according to the procedures described in WO 95/10516 published Apr. 20, 1995, U.S. Pat. No. 5,719,148 issued Feb. 17, 1998, and copending application Ser. No. 08/766,601 filed Dec. 12, 1996; the disclosures of each being incorporated herein by reference thereto; and according to the procedures described below.
Compounds of the invention can be prepared according to the reaction: 
In the reaction, the cyclic ether carboxylic acid (14.0) is coupled to the tricyclic amine (14.0) using amide bond forming conditions well known to those skilled in the art. The substituents are as defined for Formula 1.0. For example, carbodiimide coupling methods (e.g., DEC) can be used. For example, the carboxylic acid (14.0) can be reacted with the tricyclic amine (13.0) using DEC/HOBT/NMM in DMF at about 25xc2x0 C. for a sufficient period of time, e.g., about 18 hours, to produce a compound of Formula 1.0.
For example, using the carbodiimide coupling methods, compounds of the invention can be produced according to the reaction: 
The cyclic ether carboxylic acids (14.0) are prepared by methods well known in the art. Commercially available cyclic ether ketones can be reacted in a Wittig reaction to produce olefinesters. The olefin is then reduced by catalytic hydrogenation or by metal hydride reduction to the saturated cyclic ether acetates which are then hydrolyzed to the cyclic ether acids (14.0). See, for example, J. Med. Chem. (1993), 36, 2300, the disclosure of which is incorporated herein by reference thereto. The reaction is illustrated in Scheme 1 below. 
In Scheme 1, n represents 0 or 1, and Q represents O or S.
The exocyclic olefin from the Wittig reaction in Scheme 1 can be reacted with cyanide in a Michael reaction to form a nitrile, or with hydrogen peroxide to form an epoxide. The nitrile can be hydrolyzed to a carboxy group and later converted to amides. The epoxide can be hydrolyzed or reduced to an alcohol. This reaction, well known to those skilled in the art, is illustrated in Scheme 2 below. 
wherein n and Q are as defined in Scheme 1.
The cyclic ether acetates can also be produced by the insertion of an acetate carbene into a Cxe2x80x94H bond next to the ether heteroatom of a cyclic ether, as described in Tetrahedron (1989). 45, 69. The acetate carbene can be produced from a diazoacetate, such as ethyl diazoacetate, and a rhodium or copper catalyst, such as dirhodium diacetate of copper sulfate and heat. This is illustrated by the reaction: 
wherein n and Q are as defined in Scheme 1.
If the cyclic ether contains a double bond, the acetate carbene can add to the double bond to produce a bicyclocyclic ether acetate as described in Comp. Rend. (1957), 244, 2806. If the double bond is adjacent to the ether heteroatom, the resulting cyclopropyl ring can be opend by catalytic hydrogenation by an alcohol and acid. This reaction is illustrated in Scheme 3 below. 
wherein n and Q are as defined in Scheme 1.
Cyclic ethers containing a carboxy group directly attached can be prepared by a base catalyzed cyclization of a dihalo ether with diethyl malonate followed by hydrolysis and decarboxylation as described in J. Am. Chem. Soc. (1995), 115, 8401. This is illustrated by Scheme 4 below. 
wherein n and Q are as defined in Scheme 1.
Many bicyclic-cyclic ether ketones are known in the literature. Many of these can be made by Deils-Alder processes. For example, J. Am. Chem. Soc. (1978), 100, 1765 describes the the reaction: 
These bicyclic-cyclic ether ketones can be reacted in a Wittig reaction as above to produce bicyclic-cyclic ether acetates.
Compounds of Formula 13.0a 
are prepared by methods known in the art, for example by methods disclosed in WO 95/10516, in U.S. Pat. No. 5,151,423 and those described below. Compounds of Formula 13.0a wherein X is C (when the double bond is present) or CH and the C-3 postion of the pyridine ring in the tricyclic structure is substituted by bromo (i.e., R1 is Br) can also be prepared by a procedure comprising the following steps:
(a) reacting an amide of the formula 
wherein R11a is Br, R5a is hydrogen and R6a is C1-C6 alkyl, aryl or heteroaryl; R5a is C1-C6 alkyl, aryl or heteroaryl and R6a is hydrogen; R5a and R6a are independently selected from the group consisting of C1-C6 alkyl and aryl; or R5a and R6a, together with the nitrogen to which they are attached, form a ring comprising 4 to 6 carbon atoms or comprising 3 to 5 carbon atoms and one hetero moiety selected from the group consisting of xe2x80x94Oxe2x80x94 and xe2x80x94NR9axe2x80x94, wherein R9a is H, C1-C6 alkyl or phenyl;
with a compound of the formula 
wherein R1a, R2a, R3a and R4a are are independently selected from the group consisting of hydrogen and halo and R7a is Cl or Br, in the presence of a strong base to obtain a compound of the formula 
(b) reacting a compound of step (a) with
(i) POCl3 to obtain a cyano compound of the formula 
(ii) DIBALH to obtain an aldehyde of the formula 
(c) reacting the cyano compound or the aldehyde with a piperidine derivative of the formula 
wherein L is a leaving group selected from the group consisting of Cl and Br, to obtain a ketone or an alcohol of the formula below, respectively: 
(d)(i) cyclizing the ketone with CF3SO3H to obtain a compound of Formula 13.0a wherein the dotted line represents a double bond; or
(d)(ii) cyclizing the alcohol with polyphosphoric acid to obtain a compound of Formula 13.0a wherein the dotted line represents a single bond.
Methods for preparing compounds of Formula 13.0a disclosed in WO 95/10516, U.S. Pat. No. 5,151,423 and described below employ a tricyclic ketone intermediate. Such intermediates of the formula 
wherein R11b, R1a, R2a, R3a and R4a are independently selected from the group consisting of hydrogen and halo, can be prepared by the following process comprising:
(a) reacting a compound of the formula 
(i) with an amine of the formula NHR5aR6a, wherein R5a as R6a are as defined in the process above; in the presence of a palladium catalyst and carbon monoxide to obtain an amide of the formula: 
(ii) with an alcohol of the formula R10aOH, wherein R10a is C1-C6 lower alkyl or C3-C6 cycloalkyl, in the presence of a palladium catalyst and carbon monoxide to obtain the ester of the formula 
followed by reacting the ester with an amine of formula NHR5aR6a to obtain the amide;
(b) reacting the amide with an iodo-substituted benzyl compound of the formula 
wherein R1a, R2a, R3a, R4a and R7a are as defined above, in the presence of a strong base to obtain a compound of the formula 
(c) cyclizing a compound of step (b) with a reagent of the formula R8aMgL, wherein R8a is C1-C8 alkyl, aryl or heteroaryl and L is Br or Cl, provided that prior to cyclization, compounds wherein R5a or R6a is hydrogen are reacted with a suitable N-protecting group.
Compounds of Formula 1.0, wherein substituent a is NO (Ring I) and X is C or CH, can be made from compounds of Formula 13.0a using procedures well known to those skilled in the art. For example the compound of Formula 13.0a can be reacted with m-chloroperoxybenzoic acid in a suitable organic solvent, e.g., dichloromethane (usually anhydrous) or methylene chloride, at a suitable temperature, to produce a compound of Formula 13.0b 
Generally, the organic solvent solution of Formula 13.0a is cooled to about 0xc2x0 C. before the m-chloroperoxybenzoic acid is added. The reaction is then allowed to warm to room temperature during the reaction period. The desired product can be recovered by standard separation means. For example, the reaction mixture can be washed with an aqueous solution of a suitable base, e.g., saturated sodium bicarbonate or NaOH (e.g., 1N NaOH), and then dried over anhydrous magnesium sulfate. The solution containing the product can be concentrated in vacuo. The product can be purified by standard means, e.g., by chromatography using silica gel (e.g., flash column chromatography).
Alternatively, compounds of Formula 1.0, wherein substituent a is NO and X is C or CH, can be made from compounds of Formula 1.0, wherein substituent a is N, by the m-chloroperoxybenzoic acid oxidation procedure described above.
Also, alternatively, the compounds of Formula 1.0, wherein substituent a is NO and X is C or CH, can be made from tricyclic ketone compounds 
using the oxidation procedure with m-chloroperoxybenzoic acid. The oxidized intermediate compounds 
are then reacted by methods known in the art to produce compounds of the invention.
Those skilled in the art will appreciate that the oxidation reaction can be conducted on racemic mixtures and the isomers can then be separated by know techniques, or the isomers can be separated first and then oxidized to the corresponding N-oxide.
Those skilled in the art will appreciate that it is preferable to avoid an excess of m-chloroperoxybenzoic acid when the oxidation reaction is carried out on the compounds having a C-11 double bond to piperidine Ring IV. In these reactions an excess of m-chloroperoxybenzoic acid can cause epoxidation of the C-11 double bond.
(+)-Isomers of compounds of Formula 13.0a wherein X is CH can be prepared with high enantioselectivity by using a process comprising enzyme catalyzed transesterification. Preferably, a racemic compound of Formula 13.0a, wherein X is C, the double bond is present and R4 is not H, is reacted with an enzyme such as Toyobo LIP-300 and an acylating agent such as trifluoroethly isobutyrate; the resultant (+)-amide is then hydrolyzed, for example by refluxing with an acid such as H2SO4, to obtain the corresponding optically enriched (+)-isomer wherein X is CH and R3 is not H. Alternatively, a racemic compound of Formula 13.0a, wherein X is C, the double bond is present and R4 is not H, is first reduced to the corresponding racemic compound of Formula 13.0a wherein X is CH and then treated with the enzyme (Toyobo LIP-300) and acylating agent as described above to obtain the (+)-amide, which is hydrolyzed to obtain the optically enriched (+)-isomer.
Compounds of the invention, wherein a is NO and X is N, can be prepared from the tricyclic ketone (II) described above. Ketone (II) can be converted to the corresponding C-11 hydroxy compound which in turn can be converted to the corresponding C-11 chloro compound 
and (IV) can then be reacted with piperazine to produce the intermediate 
Intermediate (V) can then be reacted with the reagents, using techniques well known in the art, which will provide the desired compound.
Compounds useful in this invention are exemplified by the following examples, which should not be construed to limit the scope of the disclosure.

Combine 14.95 g (39 mmol) of 8-chloro-11-(1-ethoxy-carbonyl-4-piperidinyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridine and 150 mL of CH2Cl2, then add 13.07 g (42.9 mmol) of (nBu)4NNO3 and cool the mixture to 0xc2x0 C. Slowly add (dropwise) a solution of 6.09 mL (42.9 mmol) of TFAA in 20 mL of CH2Cl2 over 1.5 hours. Keep the mixture at 0xc2x0 C. overnight, then wash successively with saturated NaHCO3 (aqueous), water and brine. Dry the organic solution over Na2SO4, concentrate in vacuo to a residue and chromatograph the residue (silica gel, EtOAc/hexane gradient) to give 4.32 g and 1.90 g of the two product compounds 1A(i) and 1A(ii), respectively. Mass Spec. for compound 1A(i): MH+=428.2. Mass Spec. for compound 1A(ii): MH+=428.3. 
Combine 22.0 g (51.4 mmol) of the product 1A(i) from Step A, 150 mL of 85% EtOH (aqueous), 25.85 g (0.463 mole) of Fe powder and 2.42 g (21.8 mmol) of CaCl2, and heat at reflux overnight. Add 12.4 g (0.222 mole) of Fe powder and 1.2 g (10.8 mmol) of CaCl2 and heat at reflux for 2 hours. Add another 12.4 g (0.222 mole) of Fe powder and 1.2 g (10.8 mmol) of CaCl2 and heat at reflux for 2 hours more. Filter the hot mixture through celite(copyright), wash the celite(copyright) with 50 mL of hot EtOH and concentrate the filtrate in vacuo to a residue. Add 100 mL of anhydrous EtOH, concentrate to a residue and chromatograph the residue (silica gel, MeOH/CH2Cl2 gradient) to give 16.47 g of the product compound. 
Combine 16.47 g (41.4 mmol) of the product from Step B, and 150 mL of 48% HBr (aqueous) and cool to xe2x88x923xc2x0 C. Slowly add (dropwise) 18 mL of bromine, then slowly add (dropwise) a solution of 8.55 g (0.124 mole) of NaNO2 in 85 mL of water. Stir for 45 minutes at xe2x88x923xc2x0 to 0xc2x0 C., then adjust to pH=10 by adding 50% NaOH (aqueous). Extract with EtOAc, wash the extracts with brine and dry the extracts over Na2SO4. Concentrate to a residue and chromatograph (silica gel, EtOAc/hexane gradient) to give 10.6 g and 3.28 g of the two product compounds 1C(i) and 1C(ii), respectively. Mass Spec. for compound 1C(i): MH+=461.2. Mass Spec. for compound 1C(ii): MH+=539. 
Hydrolyze the product 3C(i) of Step C by dissolving in concentrated HCl and heating to about 100xc2x0 C. for @ 16 hours. Cool the mixture, the neutralize with 1 M NaOH (aqueous). Extract with CH2Cl2, dry the extracts over MgSO4, filter and concentrate in vacuo to the title compound. Mass Spec.: MH+=466.9.

Combine 25.86 g (55.9 mmol) of 4-(8-chloro-3-bromo-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidine-1-carboxylic acid ethyl ester and 250 mL of concentrated H2SO4 at xe2x88x925xc2x0 C., then add 4.8 g (56.4 mmol) of NaNO3 and stir for 2 hours. Pour the mixture into 600 g of ice and basify with concentrated NH4OH (aqueous). Filter the mixture, wash with 300 mL of water, then extract with 500 mL of CH2Cl2. Wash the extract with 200 mL of water, dry over MgSO4, then filter and concentrate in vacuo to a residue. Chromatograph the residue (silica gel, 10% EtOAc/CH2Cl2) to give 24.4 g (86% yield) of the product. m.p.=165-167xc2x0 C., Mass Spec.: MH+=506 (CI). Elemental analysis: calculatedxe2x80x94C, 52.13; H, 4.17; N, 8.29; foundxe2x80x94C, 52.18; H, 4.51; N, 8.16. 
Combine 20 g (40.5 mmol) of the product of Step A and 200 mL of concentrated H2SO4 at 20xc2x0 C., then cool the mixture to 0xc2x0 C. Add 7.12 g (24.89 mmol) of 1,3-dibromo-5,5-dimethylhydantoin to the mixture and stir for 3 hours at 20xc2x0 C. Cool to 0xc2x0 C., add an additional 1.0 g (3.5 mmol) of the dibromohydantoin and stir at 20xc2x0 C. for 2 hours. Pour the mixture into 400 g of ice, basify with concentrated NH4OH (aqueous) at 0xc2x0 C., and collect the resulting solid by filtration. Wash the solid with 300 mL of water, slurry in 200 mL of acetone and filter to provide 19.79 g (85.6% yield) of the product. m.p.=236-237xc2x0 C., Mass Spec.: MH+=584 (CI). Elemental analysis: calculatedxe2x80x94C, 45.11; H. 3.44; N, 7.17; foundxe2x80x94C, 44.95; H, 3.57; N, 7.16
Step C: 
Combine 25 g (447 mmol) of Fe filings, 10 g (90 mmol) of CaCl2 and a suspension of 20 g (34.19 mmol) of the product of Step B in 700 mL of 90:10 EtOH/water at 50xc2x0 C. Heat the mixture at reflux overnight, filter through Celite(copyright) and wash the filter cake with 2xc3x97200 mL of hot EtOH. Combine the filtrate and washes, and concentrate in vacuo to a residue. Extract the residue with 600 mL of CH2Cl2, wash with 300 mL of water and dry over MgSO4. Filter and concentrate in vacuo to a residue, then chromatograph (silica gel, 30% EtOAc/CH2Cl2) to give 11.4 g (60% yield) of the product. m.p.=211-212xc2x0 C., Mass Spec.: MH+=554 (CI). Elemental analysis: calculatedxe2x80x94C, 47.55; H, 3.99; N, 7.56; foundxe2x80x94C, 47.45; H, 4.31; N. 7.49. 
Slowly add (in portions) 20 g (35.9 mmol) of the product of Step C to a solution of 8 g (116 mmol) of NaNO2 in 120 mL of concentrated HCl (aqueous) at xe2x88x9210xc2x0 C. Stir the resulting mixture at 0xc2x0 C. for 2 hours, then slowly add (dropwise) 150 mL (1.44 mole) of 50% H3PO2 at 0xc2x0 C. over a 1 hour period. Stir at 0xc2x0 C. for 3 hours, then pour into 600 g of ice and basify with concentrated NH4OH (aqueous). Extract with 2xc3x97300 mL of CH2Cl2, dry the extracts over MgSO4, then filter and concentrate in vacuo to a residue. Chromatograph the residue (silica gel, 25% EtOAc/hexanes) to give 13.67 g (70% yield) of the product. m.p.=163-165xc2x0 C., Mass Spec.: MH+=539 (CI). Elemental analysis: calculatedxe2x80x94C, 48.97; H, 4.05; N, 5.22; foundxe2x80x94C, 48.86; H, 3.91; N, 5.18. 
Combine 6.8 g (12.59 mmol) of the product of Step D and 100 mL of concentrated HCl (aqueous) and stir at 85xc2x0 C. overnight. Cool the mixture, pour it into 300 g of ice and basify with concentrated NH4OH (aqueous). Extract with 2xc3x97300 mL of CH2Cl2, then dry the extracts over MgSO4. Filter, concentrate in vacuo to a residue, then chromatograph (silica gel, 10% MeOH/EtOAc+2% NH4OH (aqueous)) to give 5.4 g (92% yield) of the title compound. m.p.=172-174xc2x0 C., Mass Spec.: MH+=467 (FAB). Elemental analysis: calculatedxe2x80x94C, 48.69; H, 3.65; N, 5.97; foundxe2x80x94C, 48.83; H, 3.80; N, 5.97

Hydrolyze 2.42 g of 4-(8-chloro-3-bromo-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidine-1-carboxylic acid ethyl ester via substantially the same procedure as described in Preparative Example 1, Step D, to give 1.39 g (69% yield) of the product. 
Combine 1 g (2.48 mmol) of the product of Step A and 25 mL of dry toluene, add 2.5 mL of 1 M DIBAL in toluene and heat the mixture at reflux. After 0.5 hours, add another 2.5 mL of 1 M DIBAL in toluene and heat at reflux for 1 hour. (The reaction is monitored by TLC using 50% MeOH/CH2Cl2+NH4OH (aqueous).) Cool the mixture to room temperature, add 50 mL of 1 N HCl (aqueous) and stir for 5 min. Add 100 mL of 1 N NaOH (aqueous), then extract with EtOAc (3xc3x97150 mL). Dry the extracts over MgSO4, filter and concentrate in vacuo to give 1.1 g of the title compound.


Combine 16.6 g (0.03 mole) of the product of Preparative Example 2, Step D, with a 3:1 solution of CH3CN and water (212.65 mL CH3CN and 70.8 mL of water) and stir the resulting slurry overnight at room temperature. Add 32.833 g (0.153 mole) of NaIO4 and then 0.31 g (2.30 mmol) of RuO2 and stir at room temperature give 1.39 g (69% yield) of the product. (The addition of RuO is accompanied by an exothermnic reaction and the temperature climbs from 20xc2x0 to 30xc2x0 C.) Stir the mixture for 1.3 hrs. (temperature returned to 25xc2x0 C. after about 30 min.), then filter to remove the solids and wash the solids with CH2Cl2. Concentrate the filtrate in vacuo to a residue and dissolve the residue in CH2Cl2. Filter to remove insoluble solids and wash the solids with CH2Cl2. Wash the filtrate with water, concentrate to a volume of about 200 mL and wash with bleach, then with water. Extract with 6 N HCl (aqueous). Cool the aqueous extract to 0xc2x0 C. and slowly add 50% NaOH (aqueous) to adjust to pH=4 while keeping the temperature  less than 30xc2x0 C. Extract twice with CH2Cl2, dry over MgSO4 and concentrate in vacuo to a residue. Slurry the residue in 20 mL of EtOH and cool to 0xc2x0 C. Collect the resulting solids by filtration and dry the solids in vacuo to give 7.95 g of the product. 1H NMR (CDCl3, 200 MHz): 8.7 (s, 1H); 7.85 (m, 6H); 7.5 (d, 2H); 3.45 (m, 2H); 3.15 (m, 2H). 
Combine 21.58 g (53.75 mmol) of the product of Step A and 500 mL of an anhydrous 1:1 mixture of EtOH and toluene, add 1.43 g (37.8 mmol) of NaBH4 and heat the mixture at reflux for 10 min. Cool the mixture to 0xc2x0 C., add 100 mL of water, then adjust to pH≈4-5 with 1 M HCl (aqueous) while keeping the temperature  less than 10xc2x0 C. Add 250 mL of EtOAc and separate the layers. Wash the organic layer with brine (3xc3x9750 mL) then dry over Na2SO4. Concentrate in vacuo to a residue (24.01 g) and chromatograph the residue (silica gel, 30% hexane/CH2Cl2) to give the product. Impure fractions were purified by rechromatography. A total of 18.57 g of the product was obtained. 1H NMR (DMSO-d6, 400 MHz): 8.5 (s, 1H); 7.9 (s, 1H); 7.5 (d of d, 2H); 6.2 (s, 1H); 6.1 (s, 1H); 3.5 (m, 1H); 3.4 (m, 1H); 3.2 (m, 2H). 
Combine 18.57 g (46.02 mmol) of the product of Step B and 500 mL of CHCl3, then add 6.70 mL (91.2 mmol) of SOCl2, and stir the mixture at room temperature for 4 hrs. Add a solution of 35.6 g (0.413 mole) of piperazine in 800 mL of THF over a period of 5 min. and stir the mixture for 1 hr. at room temperature. Heat the mixture at reflux overnight, then cool to room temperature and dilute the mixture with 1 L of CH2Cl2. Wash with water (5xc3x97200 mL), and extract the aqueous wash with CHCl3 (3xc3x97100 mL). Combine all of the organic solutions, wash with brine (3xc3x97200 mL) and dry over MgSO4. Concentrate in vacuo to a residue and chromatograph (silica gel, gradient of 5%, 7.5%, 10% MeOH/CH2Cl2+NH4OH) to give 18.49 g of the title compound as a racemic mixture. 
The racemic title compound of Step C is separated by preparative chiral chromatography (Chiralpack AD, 5 cmxc3x9750 cm column, flow rate 100 mL/min., 20% iPrOH/hexane+0.2% diethylamine), to give 9.14 g of the (+)-isomer and 9.30 g of the (xe2x88x92)-isomer.
Physical chemical data for (+)-isomer: m.p.=74.5xc2x0-77.5xc2x0 C.; Mass Spec. MH+=471.9; [xcex1]D25=+97.4xc2x0 (8.48 mg/2 mL MeOH).
Physical chemical data for (xe2x88x92)-isomer: m.p.=82.9xc2x0-84.5xc2x0 C.; Mass Spec. MH+=471.8; [xcex1]D25=+97.4xc2x0 (8.32 mg/2 mL MeOH).

Combine 15 g (38.5 mmol) of 4-(8-chloro-3-bromo-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidine-1-carboxylic acid ethyl ester and 150 mL of concentrated H2SO4 at xe2x88x925xc2x0 C., then add 3.89 g (38.5 mmol) of KNO3 and stir for 4 hours. Pour the mixture into 3 L of ice and basify with 50% NaOH (aqueous). Extract with CH2Cl2, dry over MgSO4, then filter and concentrate in vacuo to a residue. Recrystallize the residue from acetone to give 6.69 g of the product. 1H NMR (CDCl3, 200 MHz): 8.5 (s, 1H); 7.75 (s, 1H): 7.6 (s, 1H); 7.35 (s, 1H); 4.15 (q, 2H); 3.8 (m, 2H); 3.5-3.1 (m, 4H); 3.0-2.8 (m, 2H); 2.6-2.2 (m, 4H); 1.25 (t, 3H). 
Combine 6.69 g (13.1 mmol) of the product of Step A and 100 mL of 85% EtOH/water, then add 0.66 g (5.9 mmol) of CaCl2 and 6.56 g (117.9 mmol) of Fe and heat the mixture at reflux overnight. Filter the hot reaction mixture through celite(copyright) and rinse the filter cake with hot EtOH. Concentrate the filtrate in vacuo to give 7.72 g of the product. Mass Spec.: MH+=478.0 
Combine 7.70 g of the product of Step B and 35 mL of HOAc, then add 45 mL of a solution of Br2 in HOAc and stir the mixture at room temperature overnight. Add 300 mL of 1 N NaOH (aqueous), then 75 mL of 50% NaOH (aqueous) and extract with EtOAc. Dry the extract over MgSO4 and concentrate in vacuo to a residue. Chromatograph the residue (silica gel, 20%-30% EtOAc/hexane) to give 3.47 g of the product (along with another 1.28 g of partially purified product). Mass Spec.: MH+=555.9.
1H NMR (CDCl3, 300 MHz): 8.5 (s, 1H); 7.5 (s, 1H); 7.15 (s, 1H); 4.5 (s, 2H); 4.15 (m, 3H); 3.8 (br s, 2H); 3.4-3.1 (m, 4H); 9-2.75 (m, 1H); 2.7-2.5 (m, 2H); 2.4-2.2 (m, 2H); 1.25 (m, 3H). 
Combine 0.557 g (5.4 mmol) of t-butylnitrite and 3 mL of DMF, and heat the mixture at to 60xc2x0-70xc2x0 C. Slowly add (dropwise) a mixture of 2.00 g (3.6 mmol) of the product of Step C and 4 mL of DMF, then cool the mixture to room temperature. Add another 0.64 mL of t-butylnitrite at 40xc2x0 C. and reheat the mixture to 60xc2x0-70xc2x0 C. for 0.5 hrs. Cool to room temperature and pour the mixture into 150 mL of water. Extract with CH2Cl2, dry the extract over MgSO4 and concentrate in vacuo to a residue. Chromatograph the residue (silica gel, 10%-20% EtOAc/hexane) to give 0.74 g of the product. Mass Spec.: MH+=541.0.
1H NMR (CDCl3, 200 MHz): 8.52 (s, 1H); 7.5 (d, 2H); 7.2 (s, 1H); 4.15 (q, 2H); 3.9-3.7 (m, 2H); 3.5-3.1 (m, 4H); 3.0-2.5 (m, 2H); 2.4-2.2 (m, 2H); 2.1-1.9 (m, 2H); 1.26 (t, 3H). 
Combine 0.70 g (1.4 mmol) of the product of Step D and 8 mL of concentrated HCl (aqueous) and heat the mixture at reflux overnight. Add 30 mL of 1 N NaOH (aqueous), then 5 mL of 50% NaOH (aqueous) and extract with CH2Cl2. Dry the extract over MgSO4 and concentrate in vacuo to give 0.59 g of the title compound. Mass Spec.: M+=468.7. m.p.=123.9xc2x0-124.2xc2x0 C.


Prepare a solution of 8.1 g of the title compound from Preparative Example 5. Step E, in toluene and add 17.3 mL of a 1M solution of DIBAL in toluene. Heat the mixture at reflux and slowly add (dropwise) another 21 mL of 1 M DIBAL/toluene solution over a period of 40 min. Cool the reaction mixture to about 0xc2x0 C. and add 700 mL of 1 M HCl (aqueous). Separate and discard the organic phase. Wash the aqueous phase with CH2Cl2, discard the extract, then basify the aqueous phase by adding 50% NaOH (aqueous). Extract with CH2Cl2, dry the extract over MgSO4 and concentrate in vacuo to give 7.30 g of the title compound, which is a racemic mixture of enantiomers. 
The racemic title compound of Step A is separated by preparative chiral chromatography (Chiralpack AD, 5 cmxc3x9750 cm column, using 20% iPrOH/hexane+0.2% diethylamine), to give the (+)-isomer and the (xe2x88x92)-isomer of the title compound.
Physical chemical data for (+)-isomer: m.p.=148.8xc2x0 C.; Mass Spec. MH+=469; [xcex1]D25=+65.6xc2x0 (12.93 mg/2mL MeOH).
Physical chemical data for (xe2x88x92)-isomer: m.p.=112xc2x0 C.; Mass Spec. MH+=469; [xcex1]D25=xe2x88x9265.2xc2x0 (3.65 mg/2 mL MeOH).


Combine 40.0 g (0.124 mole) of the starting ketone and 200 mL of H2SO4 and cool to 0xc2x0 C. Slowly add 13.78 g (0.136 mole) of KNO3 over a period of 1.5 hrs., then warm to room temperature and stir overnight. Work up the reaction using substantially the same procedure as described for Preparative Example 2, Step A. Chromatograph (silica gel, 20%, 30%, 40%. 50% EtOAc/hexane, then 100% EtOAc) to give 28 g of the 9-nitro product, along with a smaller quantity of the 7-nitro product and 19 g of a mixture of the 7-nitro and 9-nitro compounds. 
React 28 g (76.2 mmol) of the 9-nitro product of Step A, 400 mL of 85% EtOH/water, 3.8 g (34.3 mmol) of CaCl2 and 38.28 g (0.685 mole) of Fe using substantially the same procedure as described for Preparative Example 2, Step C, to give 24 g of the product 
Combine 13 g (38.5 mmol) of the product of Step B, 140 mL of HOAc and slowly add a solution of 2.95 mL (57.8 mmol) of Br2 in 10 mL of HOAc over a period of 20 min. Stir the reaction mixture at room temperature, then concentrate in vacuo to a residue. Add CH2Cl2 and water, then adjust to pH=8-9 with 50% NaOH (aqueous). Wash the organic phase with water, then brine and dry over Na2SO4. Concentrate in vacuo to give 11.3 g of the product. 
Cool 100 mL of concentrated HCl (aqueous) to 0xc2x0 C., then add 5.61 g (81.4 mmol) of NaNO2 and stir for 10 min. Slowly add (in portions) 11.3 g (27.1 mmol) of the product of Step C and stir the mixture at 0xc2x0-3xc2x0 C. for 2.25 hrs. Slowly add (dropwise) 180 mL of 50% H3PO2 (aqueous) and allow the mixture to stand at 0xc2x0 C. overnight. Slowly add (dropwise) 150 mL of 50% NaOH over 30 min., to adjust to pH=9, then extract with CH2Cl2. Wash the extract with water, then brine and dry over Na2SO4. Concentrate in vacuo to a residue and chromatograph (silica gel, 2% EtOAc/CH2Cl2) to give 8.6 g of the product. 
Combine 8.6 g (21.4 mmol) of the product of Step D and 300 mL of MeOH and cool to 0xc2x0-2xc2x0 C. Add 1.21 g (32.1 mmol) of NaBH4 and stir the mixture at xcx9c0xc2x0 C. for 1 hr. Add another 0.121 g (3.21 mmol) of NaBH4, stir for 2 hr. at 0xc2x0 C., then let stand overnight at 0xc2x0 C. Concentrate in vacuo to a residue then partition the residue between CH2Cl2 and water. Separate the organic phase and concentrate in vacuo (50xc2x0 C.) to give 8.2 g of the product. 
Combine 8.2 g (20.3 mmol) of the product of Step E and 160 mL of CH2Cl2, cool to 0xc2x0 C., then slowly add (dropwise) 14.8 mL (203 mmol) of SOCl2 over a 30 min. period. Warm the mixture to room temperature and stir for 4.5 hrs., then concentrate in vacuo to a residue, add CH2Cl2 and wash with 1 N NaOH (aqueous) then brine and dry over Na2SO4. Concentrate in vacuo to a residue, then add dry THF and 8.7 g (101 mmol) of piperazine and stir at room temperature overnight. Concentrate in vacuo to a residue, add CH2Cl2, and wash with 0.25 N NaOH (aqueous), water, then brine. Dry over Na2SO4 and concentrate in vacuo to give 9.46 g of the crude product. Chromatograph (silica gel, 5% MeOH/CH2Cl2+NH3) to give 3.59 g of the title compound, as a racemate. 1H NMR (CDCl3, 200 MHz): 8.43 (d, 1H); 7.55 (d, 1H); 7.45 (d, 1H); 7.11 (d, 1H); 5.31 (s, 1H); 4.86-4.65 (m, 1H); 3.57-3.40 (m, 1H); 2.98-2.55 (m, 6H); 2.45-2.20 (m, 5H). 
The racemic title compound from Step F (5.7 g) is chromatographed as described for Preparative Example 4, Step D, using 30% iPrOH/hexane+0.2% diethylamine, to give 2.88 g of the R-(+)-isomer and 2.77 g of the S-(xe2x88x92)-isomer of the title compound.
Physical chemical data for the R-(+)-isomer: Mass Spec. MH+=470.0; [xcex1]D25=+12.1xc2x0 (10.9 mg/2 mL MeOH).
Physical chemical data for the S-(xe2x88x92)-isomer: Mass Spec. MH+=470.0; [xcex1]D25=+13.2xc2x0 (11.51 mg/2 mL MeOH).


Combine 13 g (33.3 mmol) of the title compound from Preparative Example 2, Step E, and 300 mL of toluene at 20xc2x0 C., then add 32.5 mL (32.5 mmol) of a 1 M solution of DIBAL in toluene. Heat the mixture at reflux for 1 hr., cool to 20xc2x0 C., add another 32.5 mL of 1 M DIBAL solution and heat at reflux for 1 hr. Cool the mixture to 20xc2x0 C. and pour it into a mixture of 400 g of ice, 500 mL of EtOAc and 300 mL of 10% NaOH (aqueous). Extract the aqueous layer with CH2Cl2 (3xc3x97200 mL), dry the organic layers over MgSO4, then concentrate in vacuo to a residue. Chromatograph (silica gel, 12% MeOH/CH2Cl2+4% NH4OH) to give 10.4 g of the title compound as a racemate. Mass Spec.: MH+=469 (FAB). Partial 1H NMR (CDCl3, 400 MHz): 8.38 (s, 1H); 7.57 (s, 1H): 7.27 (d. 1H): 7.06 (d, 1H), 3.95 (d, 1H). 
The racemic title compound of Step A is separated by preparative chiral chromatography (Chiralpack AD, 5 cmxc3x9750 cm column, using 5% iPrOH/hexane+0.2% diethylamine), to give the (+)-isomer and the (xe2x88x92)-isomer of the title compound.
Physical chemical data for (+)-isomer: Mass Spec. MH+=469 (FAB); [xcex1]D25=+43.5xc2x0 (c=0.402, EtOH); partial 1H NMR (CDCl3, 400 MHz): 8.38 (s, 1H); 7.57 (s, 1H); 7.27 (d, 1H); 7.05 (d, 1H); 3.95 (d, 1H).
Physical chemical data for (xe2x88x92)-isomer: Mass Spec. MH+=469 (FAB); [xcex1]D25=xe2x88x9241.8xc2x0 (c=0.328 EtOH); partial 1H NMR (CDCl3, 400 MHz): 8.38 (s, 1H); 7.57 (s, 1H); 7.27 (d, 1H); 7.05 (d, 1H); 3.95 (d, 1H).

The compound 
is prepared according to the procedures of Preparative Example 40 of WO 95/10516 (published Apr. 20, 1995), by following the procedures described in Example 193 of WO 95/10516.
The (+)- and (xe2x88x92)-isomers can be separated by following essentially the same procedure as Step D of Preparative Example 4.
Physical chemical data for the R-(+)-isomer: 13C NMR (CDCl3): 155.8 (C); 146.4 (CH); 140.5 (CH); 140.2 (C); 136.2 (C); 135.3 (C); 133.4 (C); 132.0 (CH); 129.9 (CH); 125.6 (CH); 119.3 (C); 79.1 (CH); 52.3 (CH2); 52.3 (CH); 45.6 (CH2); 45.6 (CH2); 30.0 (CH2); 29.8 (CH2). [xcex1]D25=+25.8xc2x0 (8.46 mg/2 mL MeOH).
Physical chemical data for the S-(xe2x88x92)-isomer: 13C NMR (CDCl3): 155.9 (C); 146.4 (CH); 140.5 (CH); 140.2 (C); 136.2 (C); 135.3 (C); 133.3 (C); 132.0 (CH); 129.9 (CH); 125.5 (CH); 119.2 (C); 79.1 (CH); 52.5 (CH2); 52.5 (CH); 45.7 (CH2); 45.7 (CH2); 30.0 (CH2); 29.8 (CH2). [xcex1]D25=xe2x88x9227.9xc2x0 (8.90 mg/2 mL MeOH).

Following the chemistry described in J. Med. Chem., (1993), 36, 2300, a 2 L three-neck flask equipped with a thermometer, addition funnel and a nitrogen inlet tube and a magnetic stirrer was flame dried and charged with 1.0 L of anhydrous 1,2-dimethoxyethane and 9.0 g (0.38 mol) of sodium hydride (60% dispersion in oil). Triethyl phosphono-acetate, 56 g (0.25 mol), was added, dropwise with sirring, at such a rate that the reaction temperature was maintained at 20-25xc2x0 C. After addition, the reaction was stirred at 25xc2x0 C. for 45 min. then 25 g (0.25 mol) of tetrahydro-4H-pyran-4-one was added dropwise while keeping the reaction temperature at 20-25xc2x0 C. by cooling with an ice bath. After addition, the reaction was refluxed for one hour, cooled to room temperature and then poured into 4 L of ice water. This was extracted with three 2 L portions of ether. The combined ether layers were dried over magnesium sulfate and concentrated under vacuum giving 27 g of a yellow oil that is a 1:1.4 mixture of 15.0 and 16.0 as determined by NMR.
Sixteen grams of the above oil were flash chromatographed on 1.5 Kg of silica gel using ethyl acetate-hexane, 10-90, and collecting 200 mL fractions. Fractions 13-22 yielded 5.65 g of pure 15.0, ethyl tetrahydropyran-4-ylidenyl-acetate, and fractions 31-50 yielded 8.06 g of pure 16.0, ethyl 5,6-dihydro-2H-pyran-4-acetate.

A mixture of 15.0 and 16.0 (3 g, 17.6 mmol) from Preparative Example 10 was dissolved in 20 mL of ethyl acetate containing 1.0 g of 10% paladium on carbon. This mixture was stirred for 18 hours under an atmosphere of hydrogen. The catalyst was filtered and the filtrate was concentrated under vacuum giving 3.04 g of the title product as a colorless oil.

Following the procedure of Preparative Example 10, but using 2.32 g (20 mmol) of tetrahydrothiopyran-4-one instead of tetrahydropyran-4-one, 3.53 g of the product was obtained as a colorless oil.

Ethyl tetrahydrothiopyran-4-ylidenylacetate (2.3 g, 12.4 mmol), from Preparative Example 12, was dissolved in 25 mL of ethanol containing 2.34 g (61.8 mmol) of sodium borohydride. After stirring for 24 hours at 25xc2x0 C., an additional 1.2 g of sodium borohydride was added and the reaction was stirred for an additional 24 hours. Two additional 1.2 g portions of sodium borohydride were added followed by stirring for 24 hours after each addition. Silica gel TLC using hexane-ethyl acetate (95-5) showed the reaction to be complete. The reaction was treated with 200 mL of water and stirred for 5 minutes. The mixture was then extracted with three 150 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum giving 1.6 g of a colorless oil. The oil was chromatographed on 325 mL of silica gel using hexane-ethyl acetate (98-2) and 125 mL fractions were collected. Fractions 2-15 yielded 0.24 g of the product as a colorless oil.

Following a procedure described in Tetrahedron (1989), 45, 69, a 125 mL three-neck flask equiped with an addition funnel, condenser and a magnetic stirrer was charged with 25 mL of anhydrous 1,4-dioxane and 0.05 g of dirhodium diacetate. This was refluxed under nitrogen and a solution of 2.0 g (17.5 mmol) of ethyl diazoacetate in 20 mL of anhydrous 1,4-dioxane was added dropwise over a period of 130 minutes. After addition was complete, the reaction was allowed to cool to 25xc2x0 C. and filtered through a short pad of alumina and concentrated under vacuum. The residue was vacuum distilled (short path head) and the the fraction having a bp of 61xc2x0-68xc2x0 C. at 0.5 mm Hg was collected, giving 1.5 g of the product as a colorless oil.

Following the procedure of Preparative Example 14, 2.0 g (17.5 mmol) of ethyl diazo acetate was reacted with tetrahydrofuran to give 1.7 g of the product as a colorless oil, bp 84xc2x0-86xc2x0 C. at 20 mm Hg.

Following the procedure of Preparative Example 14, 2.0 g (17.5 mmol) of ethyl diazo acetate was reacted with tetrahydropyran to give 1.75 g of the product as a colorless oil, bp 95xc2x0-106xc2x0 C. at 20 mm Hg.

Following a procedure described in Comp. Rend. (1957), 244, 2806, a 100 mL three-neck flask equiped with an addition funnel, condenser and a magnetic stirrer was charged with 27.37 g (300 mmole) of 3,4-dihydro-2H-pyran and 0.08 g of anhydrous copper II sulfate. This was refluxed under nitrogen and a solution of 11.42 g (100 mmole) of ethyl diazo-acetate and 8.41 g (100 mmol) of 3,4-dihydro-2H-pyran was added dropwise over a 60 minute period. After addition was complete, the reaction was refluxed for an additional 2 hours and then allowed to cool to 25xc2x0 C. This mixture was filtered through a short pad of alumina and concentrated under vacuum. The residue was flash chromatographed on silica gel using hexane-ethyl acetate (60-40) giving 10 g of the product as a colorless oil. Silca gel TLC Rf=0.48 using the above chromatography solvent. NMR shows a mixture of 18.0 and 19.0 in an 15% to 85% ratio.

Following the procedure of Preparative Example 17, react 11.42 g (100 mmole) of ethyl diazo acetate with 2,5-dihydrofuran to give 4 g of the product as a colorless oil. Silica gel TLC Rf=0.85 (hexane-ethyl acetate 60-40).

Following the procedure of Preparative Example 17, react 11.42 g (100 mmole) of ethyl diazo acetate with 2,3-dihydrofuran to give 10.4 g of the product as a colorless oil. Silica gel TLC Rf=0.91 (hexane-ethyl acetate 60-40).

Following the procedure of Preparative Example 10 but using 5 g (52 mmol) of 4-H-pyran-4-one instead of tetrahydropyran-4-one, obtain 0.4 g of the product as a yellow solid, mp=116.5-118.7, after flash silica gel chromatography using ethyl acetate-hexane 20%-80%.

Following a procedure described in Comp. Rend. (1957), 244, 2806, if one were to hydrogenate the products of Preparative Example 17 at 750 psi and 100xc2x0 C. using Raney nickle as the catalyst then one would obtain the product.

Following a procedure described in Comp. Rend. (1957), 244, 2806, if one were to hydrogenate the products of Preparative Example 19 at 750 psi and 100xc2x0 C. using Raney nickle as the catalyst then one would obtain the product.

Following the procedure of Preparative Example 10, if one were to react 2,6-dimethyltetrahydro-4H-pyran-4-one (Recueil. (1959) 78, 91) with sodium hydride and triethyl phosphonoacetate to then one would obtain the product.

Following the procedure of Preparative Example 11, if one were to hydrogenate the product of Preparative Example 23 one would obtain the product.

Following the procedure of Preparative Example 10, if one were to react 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (J. Chem. Soc. (1944) 338) with sodium hydride and triethyl phosphonoacetate then one would obtain the product.

Following the procedure of Preparative Example 11, if one were to hydrogenate the product of Preparative Example 25 one would obtain to the product.

Following a procedure described in Liebigs Ann. Chem. (1982) 250, if one were to react ethyl tetrahydro-4-ylidenylcarboxylate, product 15.0 of Preparative Example 10, with an excess of sodium cyanide at 80-100xc2x0 C. one would obtain the product.

Following the procedure of Preparative Example 10, if one were to react 8-Oxabicyclo[3.2.1]octa-6-ene-3-one (J. Am. Chem. Soc. (1978) 100,1765) with sodium hydride and triethyl phosphonoacetate one would obtain the product.

Following the procedure of Preparative Example 11, if one were to hydrogenate the product of Preparative Example 28 one would obtain the products after separation by silica gel chromatography.

Following a procedure described in Comp. Rend. (1957), 244, 2806, if the products of Preparative Example 9 were to be reacted with boiling ethanol containing 1-2% HCl gas then the product would be obtained.

Following a procedure described in Comp. Rend. (1957), 244, 2806, if the products of Preparative Example 14 were to be reacted with boiling ethanol containing 1-2% HCl gas then the product would be obtained.

The product of Preparative Example 11 (3.04 g, 17.7 mmol) was dissoloved in 90 mL of ethanol containing 3 g (53 mmol) of potassium hydroxide. This was stirred for 18 hours and then concentrated under vacuum. The residue was dissolved in 15 mL of water, adjusted to pH 2 with 12 N HCl, and extracted with three 50 mL portions of dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum giving 2.04 g of the product as a white solid, mp=60-63xc2x0 C.
Using the hydrolysis procedure of Preparative Example 32, the esters of Preparative Examples 10-20 were hydrolyzed to the carboxylic acids identified as Preparative Examples 33 to 46 in Table 1. If one were to follow the hydrolysis procedure of Preparative Example 32, the esters of Preparative Examples 21 to 31 could be hydrolyzed to obtain the carboxylic acids identified as Preparative Examples 47-59 in Table 1.

Ethyl 2-oxabicyclo[2.2.2]-5-anti-carboxylate (a by-product produced along with 5-anti-carbomethoxy-7-anti-acetoxy-2-oxabicyclo[2.2.2]octane described in Tet. Lett. (1979) 35, 3275) was hydrolyzed following the procedure of Preparative Example 32 to give the product as a waxy solid.